PROJECT SUMMARY (DIVERSITY SUPPLEMENTAL GRANT) This minority supplemental grant is to establish a zebrafish model of cerebral amyloid angiopathy (CAA) to study lead- induced Alzheimer?s disease. The project will support a doctoral graduate student Keturah Kiper who is co-mentored by Dr. Wei Zheng and Dr. Jennifer Freeman. Cerebral amyloid angiopathy (CAA) has been implicated in the pathoetiology of Alzheimer?s disease (AD), featuring by abnormal deposition of amyloid-beta (A?) peptides in the blood vessel walls of the cortical and leptomeningeal collateral circulation networks. Recent data from this lab suggest that exposure to Pb results in excessive accumulation of A? in mouse brain, which is partly due to Pb direct interaction with A?. Such an interaction may lead to the AD pathology. Additionally, studies in literature have long established that Pb exposure causes the damage to the cerebral vasculature that constitutes the blood-brain barrier. Considering the combined effects of Pb exposure, ensuring amyloid accumulation, and brain microvascular injury, it is reasonable to postulate that Pb exposure may cause abnormal A? accumulation in cerebral vasculature and foster the CAA formation, which ultimately leads to AD pathogenesis. To better understand the mechanism, we plan to develop a zebrafish model which over-expresses amyloid peptides and use this model to test the central hypothesis that developmental exposure to low- dose Pb induces CAA pathology in the brain. We will use the Swedish mutation of APP (APP695) with the appb promoter to create this zebrafish model in our Specific Aim 1. We will characterize this model for the expression of amyloid peptides in cerebral vasculature, behavioral changes, and CAA pathology in 9-month old adult zebrafish as compared to wild type zebrafish. Upon establishing this CAA zebrafish model, We will investigate in Specific Aim 2 whether developmental exposure to Pb increases the amyloid plaque deposition in the cerebral vasculature in adult zebrafish, leading to CAA pathology and memory deficits. The study will provide the first-hand evidence that Pb-induced CAA is a step-stone for pathoetiological development of AD. Successful accomplishment of the stated project will have significant impacts on the CAA-associated AD research. First, our study will establish a novel transgenic zebrafish model not only for toxicological evaluation of Pb-induced AD, but also for future molecular mechanistic investigation of AD pathoetiology. Second, our study will explore, for the first time in literature, the concept of developmental origin of adult CAA by using Pb as a model compound. Finally, our study will establish a particular relationship between Pb exposure and CAA/AD on which to develop a possible early diagnostic method for future anti-A? therapy of CAA-associated AD, dementia, and other neurodegenerative disorders.